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1 Department of Physiology2 School of Physiotherapy, University of Otago, Dunedin, New Zealand 3 Department of Medical and Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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(Received 20 December 2006;
accepted after revision 16 March 2007; first published online 23 March 2007)
Corresponding author P. N. Ainslie: Department of Physiology, University of Otago, Dunedin, New Zealand. Email: philip.ainslie{at}stonebow.otago.ac.nz
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Introduction |
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Under normal conditions, CBF levels are matched to metabolic needs. Active mechanisms of pressure-autoregulation maintain CBF constant, despite large changes in cerebral perfusion pressure in the range of 60–150 mmHg (Paulson et al. 1990). If cerebral autoregulation is impaired, abnormally low or excessive CBF can lead to cerebral ischaemia, intracranial hypertension or even capillary damage, thus contributing to the onset of cerebrovascular events. Whilst some attenuation in cerebral autoregulation during NG-monomethyl-L-arginine (L-NMMA) infusion in humans has been reported (White et al. 2000), other studies have not confirmed this finding (Lavi et al. 2003; Zhang et al. 2004). Therefore, it is unclear whether NO is important in the autoregulation of CBF. Likewise, it is not known whether cerebral autoregulation is reduced in the morning, but such a reduction could be considered a further risk factor for high prevalence of early morning stroke, possibly as a result of a diminished oxygen supply to the brain.
The present study tested two original hypotheses in healthy humans: first, that cerebral autoregulation, in addition to cerebrovascular reactivity to CO2, is reduced in the early morning, around the time of waking, compared with measurements obtained later in the day; and second, that the early morning reduction in endothelial function (as an index of in vivo NO) as assessed by FMD would be correlated to the changes in cerebrovascular reactivity to CO2 and cerebral autoregulation. Since the available evidence supports the contributory, although not exclusive, role of endothelial-derived NO in mediating FMD and cerebrovascular reactivity to CO2 and cerebral autoregulation, any correlations between these variables may imply that these responses share a common pathway.
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Methods |
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Twenty healthy male individuals [aged 25 ± 4 years (mean ± S.D.), body mass index 24 ± 4 kg m–2] volunteered for this study, which was approved by the Lower South Regional Ethics committee and conformed to the standards set by the Declaration of Helsinki. Subjects were informed of the experimental procedures and possible risks involved in the study, and written informed consent was obtained. Subjects were not taking any medication, all were non-smokers, and none had any history of cardiovascular, cerebrovascular or respiratory disease.
Experimental design
Prior to the experimental testing, all subjects were fully familiarized with all experimental procedures (between 6 and 8 pm). Subjects were instructed to abstain from exercise and alcohol 24 h prior, and not to eat a heavy meal or consume caffeine 4 h prior to experimental testing. Experimental testing was carried out in the evening (between 6 and 8 pm), and the following morning (between 6 and 8 am), 30 min after awakening. All variables were recorded continuously into a computer for off-line analysis. Following the evening tests, subjects underwent an overnight domiciliary sleep study to ensure adequate sleep quality and exclude obstructive sleep apnoea or other sleep pathology. Subjects were awakened at 05.30 am, and testing began at 06.00 am.
Measurements of CBF velocity, arterial blood pressure (BP) and cortical oxygenation. Blood flow velocity in the right middle cerebral artery (MCAv) was measured using a 2 MHz pulsed Doppler ultrasound system (DWL Doppler, Sterling, VA, USA) using search techniques described elsewhere (Aaslid et al. 1982). Beat-to-beat arterial BP was monitored using finger photoplethysmography (Finometer, TPD Biomedical Instrumentation, Amsterdam, The Netherlands). Frontal cortical oxyhaemoglobin concentrations were monitored non-invasively using near-infrared spectroscopy (NIRS; NIRO-200; Hamamatsu Photonics KK; Hamamatsu, Japan; Mehagnoul-Schipper et al. 2000). A probe holder containing an emission probe and a detection probe was attached at the right side of the forehead with a distance of 5 cm between the probes. The methodology of this system has been previously described (Nollert et al. 1995). The NIRO-200 measures the concentration changes of oxyhaemoglobin, deoxyhaemoglobin and total haemoglobin using a modified Beer-Lambert law (Al-Rawi et al. 2001). It gives an absolute unit (micromoles per litre) for the changes in oxy- and deoxyhaemoglobin by incorporating an optical path length. In the brain, oxyhaemoglobin, deoxyhaemoglobin and total haemoglobin were measured simultaneously every 1 s throughout the experiment, and expressed as the magnitude of the change from the initial value. End-tidal CO2 (PET,CO2) was sampled from a leak-free mask and measured by a gas analyser (model CD-3A CO2 analyser, AEI Technologies, Pittsburgh, PA, USA). All data were acquired continuously at 200 Hz using an analog-to-digital converter (Powerlab/16SP ML795; ADInstruments, Colorado Springs, CO, USA) interfaced with a computer. Data were sampled at 200 Hz and stored for subsequent analysis using commercially available software (Chart version 5.02, ADInstruments).
Orthostatic challenge. Following instrumentation, subjects remained supine for 20 min before 5 min of steady-state baseline recordings were obtained. Then, the subjects stood up and remained in the free-standing position for 3 min. At all times, frontal cortical oxygenation, MCAv, arterial BP and PET,CO2 were continuously monitored. During both the supine rest and stand, subjects were instructed to keep their hand at waist level. The Finometer uses a height correction system, whereby any changes in vertical displacement of the finger cuff relative to the heart are corrected for by a reference probe placed on the chest at the fourth intercostal space in the midclavicular line (heart level).
Cerebral autoregulation.
A cerebral autoregulation index (ARI) was calculated in triplicate from continuously recorded MCAv and BP using the thigh cuff inflation–deflation method (Aaslid et al. 1989). Briefly, leg cuffs were placed on the quadriceps muscles of both thighs and inflated to approximately 30 mmHg greater than the recorded systolic BP for 2 min, then rapidly deflated. This deflation produces a sudden, transient decrease in mean BP of approximately 15–25 mmHg, which is considered to be the dynamic cerebral autoregulation stimulus. Approximately 4 min was allowed between each thigh cuff deflation; on average, however, BP returned to baseline within 
60 s (range: 41–122 s) of deflation. We calculated a dynamic rate of regulation, which expresses the rate of restoration of MCAv with respect to the decrease in MAP, and derived an ARI using a previously reported algorithm and software (Tiecks et al. 1995). The ARI varies between zero (absence of autoregulation) and nine (best autoregulation), and tends to be around five for healthy subjects (Tiecks et al. 1995).
Hypercapnic challenge.
Following an 8 min baseline period of breathing room air, the inspirate was rapidly (4 s) changed to 5% CO2 with 21% O2 and a balance of nitrogen for 3 min. The last minute of each exposure was used for data analysis. The hypercapnia cerebral vascular reactivity was characterized as the slope of the linear regression fitted to the percentage change in MCAv from baseline per millimetre of mercury increase in PET,CO2.
Endothelial function.
Endothelial function was evaluated by ultrasound measures of flow-mediated endothelium-dependent vasodilatation (FMD) and glyceryltrinitrate-induced endothelium-independent vasodilatation (NFMD) of the brachial artery (Celermajer et al. 1992). The right brachial artery images were acquired above the antecubital fossa using a Sonos 2000 ultrasound machine (Hewlett-Packard, Andover, MA, USA) and a high-resolution 7.5 MHz linear array transducer (Hewlett-Packard, Andover, MA, USA). When the first baseline images were obtained, the skin was marked so that the artery could be scanned at the same place in subsequent studies. A continuous ECG was recorded for timing diastole. Reactive hyperaemia (FMD) was induced by rapid inflation of a BP cuff (5 cm) around the wrist to 250 mmHg for 5 min, then released. The diameter of the brachial artery was then assessed for 60–90 s after rapid deflation of the cuff. Endothelium-independent vasodilatation was assessed 3–4 min following a single sublingual dose of nitroglycerin (0.4 mg). The percentage change due to FMD and NFMD was expressed relative to baseline. All images were acquired by the same experienced investigator, stored digitally, and the analysis made by two double-blinded investigators. The interobserver reproducibility was 95%.
Sleep studies. All sleep studies were carried out with a Compumedics portable system (PS2; Melbourne, Australia). The portable sleep system allowed the collection of 13 channels of data, very similar in scope to that available in the sleep laboratory: one channel of ECG; two channels of EEG; two channels of electro-oculogram; one channel of submental EMG; one channel of leg movement; one channel of body position; two channels of respiratory displacement (thoracic and abdominal displacement by inductance plethysmography); one channel of snoring; one channel of nasal flow signal via nasal cannula; and one channel of saturation by digital pulse oximetry (saturation accuracy ±2% between 70 and 100% with finger probe). The subjects were set up for the polysomnogram and manually scored according to standard format (Rechtschaffen & Kales, 1990).
Statistical analysis
All data were analysed using the SPSS social statistics package (version 9, Guildford, UK). A Shapiro–Wilks test was applied to each dependent variable to mathematically assess distribution normality. Statistical comparisons between evening and morning measurement were performed using Student's paired t test. For the supine-to-stand test, a two-way mixed factor ANOVA was incorporated to examine the effects of trial, time and state on selected variables. Significance for all two-tailed tests was established at an 
level of P < 0.05, and data are expressed as a means ±
S.D.
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Results |
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Owing to technical problems, brachial artery flow-mediated dilatation data (FMD and NFMD) were obtained in 17 out of 20 participants. All subjects were observed to have normal sleep architecture, did not snore and had no sleep-disordered breathing.
Early morning impairment in cerebral autoregulation, reactivity and endothelial function
From evening to morning, there was a significant decrease in ARI (5.23 ± 0.55 versus 4.7 ± 0.56 a.u.; P < 0.05; Fig. 1A), MCAv reactivity to CO2 (5.28 ± 0.6 versus 4.64 ± 1.1% mmHg–1; P < 0.05; Fig. 1B) and FMD (7.60 ± 0.85 versus 5.98 ± 1.44%; P < 0.05; Fig. 1C). The average dynamic BP changes achieved by the thigh cuff release were not different between evening and morning (–22 ± 7 versus –21 ± 6 mmHg, respectively; n.s.). Likewise, there were no overnight differences in baseline PET,CO2 (41.1 ± 2.9 versus 40.8 ± 2.1 mmHg). The lowered FMD was related to the decrease in MCAv reactivity to CO2 (r = 0.76; P < 0.05; Fig. 2A), but not to the decrease in ARI (r = 0.11; n.s.; Fig. 2B). There were no relationships between the early morning decrease in MCAv reactivity to CO2 and ARI or NFMD (n.s.; data not shown). Percentage changes in brachial artery diameter after nitroglycerin (NFMD) were similar at the two time points (16.18 ± 1.86% morning versus 17.1 ± 2.2% evening; n.s.; Fig. 1D). The brachial artery diameter before the hyperaemic stimulus did not differ between the evening and early morning (4.4 ± 0.1 versus 4.4 ± 0.2 mm, respectively; n.s).
Postural changes during supine-to-stand challenge
Figure 3 illustrates a transient decrease in morning MCAv and cortical oxyhaemoglobin concentrations (Fig. 3A and B) that occurred in response to assuming a supine-to-upright position (P < 0.05 versus evening), despite similar alterations in PET,CO2 and BP (Fig. 3C and D). There were no overnight differences between cortical deoxyhaemoglobin or total haemoglobin (data not shown).
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Discussion |
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This is the first study to monitor overnight changes in cerebral autoregulation and cerebral haemodynamic changes during an orthostatic challenge. The early morning attenuation in MCAv and oxygenation during standing, combined with a reduced ARI, may render the brain vulnerable to potential changes in BP, thereby facilitating the onset of cerebrovascular accidents. Our observation of significant reductions in PET,CO2 and MCAv during a supine-to-stand challenge is consistent with values reported previously during the development of postural hypocapnia (Gisolf et al. 2004) and a related reduction in MCAv (Immink et al. 2006). Adequate maintenance of cerebral perfusion during physiological challenges, such as orthostasis, is of utmost importance to maintain brain function and to avoid cerebral hypoxia and loss of consciousness. It seems reasonable to speculate that such a reduction in cerebral autoregulation at rest and during a postural change may have significant implications for early morning stroke, especially in more ‘at-risk’ groups.
The underlying mechanisms of cerebral autoregulation are unknown, but probably comprise a complex interaction of neural, metabolic and myogenic factors (Paulson et al. 1990). Interestingly, although cerebral autoregulation (as assessed using the thigh deflation technique) has been shown to be attenuated during L-NMMA infusion in one human-based study (White et al. 2000), other studies have not confirmed this finding (Lavi et al. 2003; Zhang et al. 2004). The findings of the present study are consistent with the view that NO is not a major factor involved in the autoregulation of CBF (Lavi et al. 2003, 2006; Zhang et al. 2004).
The relationship between a reduction in NO bioavailability as assessed by FMD and CO2-induced vasodilatation (Fig. 2), although not cause and effect, suggests that NO may play a functional role in MCAv reactivity to CO2. In a number of studies, the cerebral vasodilatory response to hypercapnia has been inhibited by L-arginine analogues (Bonvento et al. 1994; Iadecola & Zhang, 1994; Wang et al. 1994, 1995; Thompson et al. 1996), suggesting the involvement of NO. However, results have not been consistent, with differences in sensitivity to NO synthase inhibitors described within and between species (Goadsby, 1994; Wang et al. 1994; McPherson et al. 1995), including humans (White et al. 1998). In contrast to some results in animals, White et al. (1998) found no effect of NO synthase inhibitor on cerebrovascular reactivity to CO2, as assessed by internal and common carotid artery volume flow and middle cerebral artery flow velocity. Although NO inhibition was reported to cause vasoconstriction in the middle cerebral artery, it was not apparent whether changes in the diameter of the internal and common carotid artery also occurred (White et al. 1998). It should also be recognized that a number of studies in humans have used weak inhibitors of NO synthase (NOS) and that doses of L-NMMA may not have been high enough to inhibit the enzyme fully. Thus, it is possible that the role of NO in previous human studies is underestimated. In summary, our results are broadly consistent with recent reports that endothelial-derived NO is involved in CO2-dependent CBF regulation, which depends on integrity of the vascular endothelium (Silvestrini et al. 2000; Lavi et al. 2003; Krainik et al. 2005).
On the basis of our experimental approach, whilst acknowledging the limitation that correlational analysis does not necessary imply cause and effect, the relationships between MCAv reactivity to CO2 and FMD provide support for the idea that CO2 reactivity could be a surrogate of local cerebrovascular endothelial function in otherwise healthy humans free of pathology, in addition to humans with overt endothelial dysfunction (Lavi et al. 2006). Whilst the present study is limited to non-invasive findings in humans, we suggest that other points are pertinent to consider. First, although NOS inhibitors can attenuate FMD, reactive hyperaemia is an integrated response involving adenosine, potassium, pH and NO. Although a previous study has shown that FMD, assessed in the brachial artery following occlusion at the wrist (as used in the present study) before and during L-NMMA inhibition, is mediated exclusively by NO (Doshi et al. 2001), the apparent 20% diurnal variation in FMD could be the result of subtle variation in the signalling pathway of these other mediators and not solely of endothelial-derived nitric oxide synthase (eNOS) activity. Second, although cerebrovascular CO2 reactivity is primarily mediated by extracellular pH, it can also be modulated by cyclo-oxygenase activity and by NO (Andresen et al. 2006). When NO modulates CO2 reactivity in certain animal species, it does so as a permissive enabler (Iadecola & Zhang, 1996). This permissive effect appears to depend on neuronal-derived nitric oxide synthase (nNOS) rather than eNOS because: (1) the CO2 response is inhibited by 7-nitroindazole (7-NI) in rats; (2) NG-nitro-L-arginine (L-NNA) has no effect on the CO2 response in nNOS null mice (Irikura et al. 1995); and (3) L-NNA still inhibits the CO2 response in eNOS null mice (Ma et al. 1996). Moreover, at least in animal studies, NOS activity needs to be inhibited by > 50% to produce a reduction in CO2 reactivity (Irikura et al. 1994). It seems unlikely that NOS activity decreases by > 50% in the morning. Therefore, although species differences may exist, a small diurnal change in eNOS activity is not expected to have a significant effect on CO2 reactivity. Collectively, considering both human and animal studies, it seems that the regulation of cerebral vasculature is far from resolved and that the mediators of vascular regulation may prove to be different between the two vascular beds; the possibility that eNOS is a common mechanism between different vascular beds in the human body warrants further investigation, potentially by incorporating combined techniques involving L-NMMA, L-arginine and sodium nitroprusside to investigate the role eNOS may be playing in the decreased morning FMD, CO2 reactivity and/or autoregulation.
Methodological considerations
A potential limitation of the dynamic thigh cuff deflation technique is that it determines the cerebrovascular response to a reduction in arterial BP, whereas a relevant question may be related to the cerebrovascular response to an increase in arterial BP. However, dynamic cerebral autoregulation (CA) as assessed using the thigh cuff deflation technique has been shown to correlate closely with findings of static autoregulation testing (Tiecks et al. 1995), which induces a sustained increase in arterial BP. Although photoplethysmography measurements correlate well with intra-arterial measurements during experimental manipulations of arterial BP (Parati et al. 1989), the possibility exists that the thigh cuff deflation may provoke some peripheral vasoconstriction, causing a transient underestimate of BP. We feel that this effect is unlikely to influence our results for the following reasons. First, the thigh-deflation hypotensive stimulus was the same between evening and morning (–22 ± 7 versus –21 ± 6 mmHg, respectively; n.s.). Second, our hypotensive stimulus is comparable to that recorded by direct intra-arterial measurement (Aaslid et al. 1989; Tiecks et al. 1995). Third, the absence of a difference in the BP trends upon assuming the upright posture supports the hypothesis that the differences in MCAv and cerebral oxyhaemoglobin do reflect an altered cerebral vascular response rather than an altered stimulus presentation to the cerebral circulation. This hypothesis is based, in part, on the assumption that there were no differences in intracranial venous pressure dynamics between evening and morning measurements. Fourth, we used Doppler ultrasound to measure flow velocity, rather than blood flow, in the MCA. Nevertheless, the majority of research indicates that MCAv is a reliable index of CBF (Kirkham et al. 1986; Giller et al. 1993; Valdueza et al. 1997; Serrador et al. 2000). Since there were no overnight changes in either end-tidal CO2 or blood pressure at rest or during the postural manoeuvres, this alone would not explain a selected influence of these variables on MCA diameter, suggesting that such changes do not complicate the interpretation of the main findings in the present study. An important consideration is whether steady-state MCAv was reached during the last minute of the 3 min hypercapnia step. The MCAv changes and reactivity reported in this study are comparable with those of previous studies using 90 s increments in end-tidal CO2 (Ide et al. 2003) or using 5 min incremental steps of inspired CO2 (Xie et al. 2006), suggesting that the 180 s steps of hypercapnia are sufficiently long for the MCAv responses to unfold. Finally, it is also important to note that the relative compartmentalization of brain NO production and NO synthase isoenzymes in humans is not known; therefore, interpretation of the findings of the present study may be confounded by the presence of neuronal NO, as well as other vasoactive factors interacting with the endothelial NO in the cerebral circulation (Faraci & Heistad, 1998).
Potential strengths of our study should also be considered. Polysomnographic-monitored sleep was used to confirm adequate sleep quality and to rule out the possibility of any sleep-related pathology. This was important since inadequate sleep and/or sleep apnoea can independently impair vascular function (Kato et al. 2000a,b). Furthermore, since overnight abstinence from vasoactive medication may also affect the early morning vascular measurements, we used otherwise unmedicated healthy volunteers. It remains, however, to be established whether the present observations in healthy young volunteers can be used as possible explanations of cardiovascular events in at-risk groups. Finally, the full familiarization of each subject and the selective early morning impairment of FMD but not NFMD are consistent with our observations and support the conclusions of a reduction in early morning cerebral autoregulation and MCAv reactivity to CO2. Collectively, the study design and strengths make our findings robust and unlikely to reflect artifact.
Conclusion
In conclusion, a reduction in NO availability may, in part, be responsible for the previously reported reduction in MCAv reactivity to CO2. Early morning impairment in cerebrovascular reactivity to CO2 and cerebral autoregulation may facilitate the onset of cerebrovascular accidents; this may be of particular relevance to at-risk groups, such as the elderly or those with sleep-disordered breathing (Yaggi et al. 2005), especially upon resuming the upright position.
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